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Myocarditis in cancer patients is caused by specific immune cells: Study

by Pragati Singh

Researchers from UC San Francisco and Vanderbilt University Medical Center discovered specific immune cells that cause deadly heart damage in a subset of cancer immunotherapy patients in a new study. The researchers also discovered the cells in heart muscle that are targeted by the damaging immune cells, and their new results have already prompted them to start looking for better ways to prevent or cure this potentially fatal heart inflammation known as myocarditis. The kind of myocarditis they investigated is a rare but lethal adverse effect of cancer immunotherapy medications known as immune checkpoint inhibitors (ICIs).

ICIs target proteins in the body that act as gatekeepers for immune system responses, therefore preventing undesired inflammation. However, inhibiting these checkpoint proteins with ICIs slows immunological responses, allowing the immune system to more efficiently target established malignancies. Many cancer patients have been saved by ICI therapy.
According to Javid Moslehi, MD, William Grossman Distinguished Professor and Section Chief of Cardio-Oncology and Immunology at the UCSF Heart and Vascular Center, less than 1% of patients who get checkpoint inhibitor therapy, which was originally licenced in 2011, suffer myocarditis. However, over half of those who do undergo this inflammatory immune response die as a result.

Moslehi collaborated on the new study, which will be published in Nature on November 16, 2022, with cancer scientist Justin Balko, PharmD, PhD, an associate professor of medicine and pathology at Vanderbilt. In 2016, they reported the clinical syndrome of ICI-myocarditis for the first time.

In the latest investigation, the researchers employed a line of mice in which the same proteins targeted by ICIs in humans were genetically knocked out to replicate human ICI-caused myocarditis. They discovered that immune system cells known as CD8 T lymphocytes dominated in inflamed cardiac tissue from mice with myocarditis.
The researchers concluded that these same activated T cells are required to cause myocarditis in ICI-treated cancer patients, and hence immunosuppressive medications that impact CD8 T cells may be advantageous.

“We earlier observed many T cells in patients who had died, but in the mice we performed several key experiments to show that the T lymphocytes really are drivers of the disease process, and not merely innocent bystanders,” Moslehi said.

“There are therapeutic implications to this study.” The research team has already published a case study in which they employed Abatacept, a rheumatoid arthritis medicine that inhibits CD8 T cell activation, to successfully treat myocarditis in a cancer patient.

The authors revealed in the Nature article that the CD8 T cells that were preferentially activated and multiplied in a clone-like form in myocarditis were those that targeted alpha-myosin heavy chain, a critical protein involved in muscle contraction in the heart (alpha-MHC).

The researchers subsequently studied biopsy and postmortem tissue from three ICI-treated cancer patients with myocarditis and discovered that the most common CD8 T cells that had developed clonally in humans were those that targeted alpha-MHC.

“What was interesting is that the T cell receptors, which are basically identity barcodes of the T lymphocytes, that were specific for alpha-MHC were identical in the affected hearts, meaning that they were likely going after the same target,” said Balko.


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